The present invention relates to methods and compositions for the treatment of insulin resistance, diabetes, and/or diabetes associated dyslipidemia.
Diabetes is the fifth leading killer of Americans, with 73,000 deaths per year. Diabetes is a disease in which the body's failure to regulate glucose, or blood sugar, can lead to serious and even fatal complications. There are two types of diabetes, type 1 and type 2.
Type 2 diabetes is a metabolic disorder that is primarily characterized by insulin resistance, relative insulin deficiency, and hyperglycemia. Insulin resistance is defined as a decreased response of peripheral tissues to insulin action. Increasingly, insulin resistance has been recognized as the integral feature of metabolic syndrome, which includes glucose intolerance, insulin resistance, obesity, dyslipidemia, hypertriglyceridemia, low high density lipoprotein (HDL) cholesterol, hypertension, and accelerated atherosclerosis. Hyperinsulinemia and delayed clearance of glucose in an oral glucose tolerance test (OGTT) are hallmarks of insulin resistance in patients.
Typically, subjects suffering from type 2 diabetes are also likely to have dyslipidemia (i.e., diabetic dyslipidemia), where the subjects have abnormally low levels of HDL and/or abnormally high levels of low density lipoprotein (LDL), cholesterol, and/or abnormally high levels of triglycerides. Type 2 diabetic subjects may have a preponderance of smaller, denser LDL particles, which can also possibly increase atherogenicity even if the absolute concentration of LDL cholesterol is not abnormally high. The low levels of HDL (i.e. <40 mg/dL) and/or high levels of LDL (i.e. >100 mg/dL) and/or high levels of triglycerides (i.e. >150 mg/dL) increase the risk of atherosclerosis and the risk for developing cardiovascular disease in the diabetic population. For further information, see the National Cholesterol Education Program (NCEP) update on the Adult Treatment Panel (ATP) III guidelines, Circulation; 110:227-239 (2004).
Niacin (Vitamin B3) is a water-soluble vitamin whose derivatives play essential roles in energy metabolism in the living cell and in DNA repair. Other functions of niacin include removing toxic chemicals from the body and assisting in the production of steroid hormones. Niacin, when taken in large doses, blocks the breakdown of fats in adipose tissue, thus altering blood lipid levels. Niacin is used in the treatment of dyslipidemia because it reduces very low density lipoprotein (VLDL), a precursor of LDL cholesterol. Because niacin blocks the breakdown of fats, it causes a decrease in free fatty acids in the blood and consequently, decreased secretion of VLDL and cholesterol by the liver.
By lowering VLDL levels, niacin also increases the level of HDL or “good” cholesterol in blood, and therefore, it is sometimes prescribed for patients with low HDL, who are also at high risk of a heart attack.
High dose niacin has been shown to elevate fasting blood sugar levels, thereby worsening type 2 diabetes. Accordingly, niacin is contra-indicated for persons with type 2 diabetes. The mechanism behind niacin-induced insulin resistance and diabetes is presently unknown. It is believed, however, that insulin actions are mediated by insulin receptors present in tissues that utilize glucose and it is conceivable that impaired receptor signaling in the presence of niacin may contribute to niacin-induced insulin resistance.
Patients taking pharmacological doses of niacin (ranging from 0.5-3 g per day) often experience an array of side effects that can include one or more of dermatological complaints (facial flushing and itching, dry skin, and skin rashes including acanthosis nigricans). Facial flushing is the most commonly reported side effect of niacin and is so severe that many patients discontinue niacin treatment as a result. The flushing has been shown to be caused by the result of cutaneous vasodilation resulting from niacin induced release of prostaglandins (e.g., prostaglandin D2, (PGD2)) in the skin.
Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a heterogeneous group of medications with analgesic, antipyretic, and anti-inflammatory actions. These drugs are widely used to control fever and acute or chronic pain. They are the most sold medications worldwide and, together with analgesics and antipyretics, account for approximately 30% of all medicines used.
NSAIDs are typically contra-indicated for diabetes sufferers, demonstrating some incidence of gastrointestinal bleeds in patients taking NSAIDS. Some NSAIDs have been shown to exacerbate insulin resistance. See e.g., Pereira Arias, A., et. al., Horm. Meta. Res. 2001:33(11); 659-63; and Pereira Arias, A., et al., Metabolism. 2000:49(7): 839-44; and Dekker, E., et. al., Metabolism, 1998; 47(2): 217-22.
Meloxicam is a NSAID that is used to relieve the symptoms of arthritis, primary dysmenorrheal, fever, and as an analgesic, especially where there is an inflammatory component. Meloxicam has been shown to significantly decrease symptoms of pain and stiffness in patients, with a low incidence of gastrointestinal side effects. In models, it exhibits anti-inflammatory, analgesic, and antipyretic activities. Its mechanism of action may be related to Cox inhibition. Meloxicam has been shown, to inhibit Cox-2 preferentially over Cox-1 to some degree.